a chemical formula of C51H79NO13, and in solution, forms a structural trans-isomer and cis-isomer at a ratio of 4:1 (in chloroform solution) due to steric hindrance in vicinity of pipecolate amide bond. Rapamycin is hardly dissolved in water, aliphatic hydrocarbon, and diethylether, but is dissolved in alcohol, halogenated hydrocarbon, and dimethylsulfoxide. Rapamycin in a solution state is unstable in plasma and in a low-pH and neutral-pH buffer solution, at a temperature of 37° C., and decomposes with a half lifetime of less than 10 hours.
In particular, rapamycin has various bioactivities, such as an antifungal activity, an anti-cancer activity, and an immunosuppressive activity, and furthermore, it has been reported as a lifespan prolongation drug. Also, rapamycin is used as a coating agent for medical devices, such as a stent.
However, rapamycin has low bioavailability and solubility. To overcome such disadvantages, many rapamycin derivatives have been synthesized: carboxylic acid esters (PCT WO 92/05179), carbamates (U.S. Pat. No. 5,118,678), carbonate (U.S. Pat. No. 5,260,300), amide ester (U.S. Pat. No. 5,118,678), fluorinated esters (U.S. Pat. No. 5,100,883), acetal (U.S. Pat. No. 5,151,413), silyl ethers (U.S. Pat. No. 5,120,842), bicyclic derivatives (U.S. Pat. No. 5,120,725), rapamycin dimers (U.S. Pat. No. 5,120,727), and O-aryl, O-alkyl, O-alkenyl, and O-alkynyl derivatives (U.S. Pat. No. 5,258,389), and various rapamycin drug precursors (U.S. Pat. No. 5,672,605, U.S. Pat. No. 5,583,139, U.S. Pat. No. 5,527,907, U.S. Pat. No. 5,457,111, U.S. Pat. No. 5,955,100, U.S. Pat. No. 6,146,658, and U.S. Pat. No. 5,935,995).
However, there is still a limit on the development of a drug with improved bioavailability based on an increase in solubility of rapamycin. Accordingly, the development of a drug that improves the solubility of rapamycin is needed.